During the 1950's and 1960's many pharmaceutical concerns launched extensive programs to synthesize modified corticosteroids. The objective was to create systemically active compounds having more potent anti-flammatory activity than the naturally occuring corticoids but without correspondingly elevated levels of side effects such as interference with the pituitary-adrenal relationship (leading to adrenal insufficiency) and effects on electrolyte balance and glucose metabolism.
The initial efforts resulted in certain quite potent compounds of the prednisolone series having a 9.alpha.floro constituent in combination with 16-.alpha. or .beta.-methyl or 16.alpha.hydroxy substitution, such as Betamethasone, dexamethasone, and triamcinolone. Certain compounds having 16-.alpha.methyl substitution along with a 6.alpha.floro substituent (paramethasone) or with combined 6.alpha., 9.alpha.floro substitution (flumethasone) also proved interesting. Prednisolone derivitives having a 6.alpha.floro substituent and 16.beta.-methyl substitution were apparently not explored and these are the subjects of this invention. In the above noted prior art compounds, the problem of electrolyte imbalance (primarily sodium retention with potassium depletion) was substantially reduced. Various theories were advanced for this with one or more groups being said to enhance potency (.DELTA.' and 9.alpha.F) either with (9.alpha.F) or without (.DELTA.') some degree of potentiation of mineralcorticoid activity and with other substituents (16-OH,.alpha.CH.sub.3 or .beta.CH.sub.3) being said to attenuate somewhat the mineralcorticoid effect. In any event, when the lower doses made possible by enhanced potency were used, observed electrolyte activity was reduced and it is generally accepted today that at therapeutic doses the compounds which are .DELTA.'.sup.4 dienes with 6.alpha. and/or 9.alpha.halogen substitution combined with 16-methyl or 16.alpha.hydroxy substitution do not cause an unacceptable degree of electrolyte imbalance.
Despite these early successes, significant separation of other side effects, such as glycogen diposition, from therapeutic activity proved difficult. It was later noted that in some cases the 16.alpha.methyl substitution could, by itself, be employed to augment anti-inflammatory activity somewhat more than glycogen deposition and that 16.beta.methyl substitution could be employed to diminish glycogenic properties somewhat without altering the anti-inflammatory activity.
The above noted first prepared modified cortosteroids and their esters and other derivatives are still widely used today in various forms, and betamethasone and its esters still represent today almost one-third of the prescriptions written in the United States for topical steroids. Dexamethasone, fluromethasone and paramethasone are also still used clinically today, although to a much lesser degree.
Despite: (1) the above general and accepted statements about the relationship of structure and biological activity (2) the initial and continued success for almost twenty years of Betamethasone (9.alpha.difloro 16.beta.-methyl prednisolone) and its esters as topical anti-inflammatory agents and (3) the use for over a decade of paramethasone acetate (6.alpha.Floro-16.alpha.methyl-prednisolone-21-acetate) as a systemic anti-inflammatory agent, there remarkably appears to have been no discovery of the 6.alpha.-floro-16.beta.-methyl-prednisolone or its esters.
In the mid-1960's, attention turned to attempts at development of highly effective topical corticoids with little or no systemic effects. The former objective was pursued through a combination of potentiated anti-inflammatory activity per se and/or improved absorption through the stratum corneum. The latter objective was pursued through reduction of systemic activity per se and/or reduction in the ability to migrate from the epidermis into the dermis after penetration of the stratum corneum.
Two important corticoids developed at that time which are still major factors today are the 16-17 acetonides of Triamcinolone and its 6.alpha., 9.alpha.difloro counterpart, fluocinolone. For some reason, still not fully understood, triamcinolone acetonide is about ten times as active as Triamcinolone topically, but only equiactive systemically. Fluocinolone acetonide is essentially ineffective systemically even though it is perhaps even more active topically than its Triamcinolone counterpart. For topical steroids these compounds plus related Fluandrenalone (6.alpha.F, 16.alpha.OH, hydrocortisone 17,21 acetonide) today represent more than one half of all prescriptions in the United States. While due to the acetonide formation they differ significantly in structure from the compounds of this invention, they are mentioned here because of their importance in the overall mileau.
At the end of the 1960's, much attention was given to the esters of the earlier discussed compounds and of other compounds, such as beclomethasone (the resulting dipropionate), which had not found earlier commercial use. In some, but by no means all instances, the esterification at 17 and/or 21 was found to improve the potency of therapeutic effect as evaluated by Vasoconstriction assays. What is most striking from the literature of that time is the unpredictability of the results of esterification when trying to apply knowledge gained with one skeletal series to another skeletal series. Mostly this is due to the subtle alteration of the shapes of molecules caused by even minor structural differences and it is on the basis of shape that hormones are recognized by their receptors.
One of the most completely explored series of esters is those of Betamethasone (9.alpha.F, 16.beta.- CH.sub.3). When esterified in the 17 position, betamethasone is potentiated from activity of 1% of fluocinalone acetonide to up to 350% of fluocinolone acetonide as the ester chain increases from acetate through butyrate and propionate up to valerate, the latter compound being one of the most widely used topical anti-inflammatory agents today. The 17-benzoate, U.S. Pat. No. 3,529,060, has recently been found to be of equal activity to the valerate. Esterification in the 21-position also causes some potentiation of anti-inflammatory activity, but primarily imparts more long acting effects as was expected, from early findings, mentioned previously, on the 21-acetates of betamethasone. As noted earlier, the esters of Betamethasone today represent almost one-third of prescriptions for topical steroids in the United States.
Another series receiving a lot of attention were the 6,9 difloroprednisolones (16 unsubstituted) through the work of Gardi, et al described for example in the Journal of Medicinal Chemistry, 15, 556 (1972) and 15,783 (1972), in Steroids, 16:6, 663 (1970), and in U.S. Pat. Nos. 3,780,177 (6,9 difloroprednisolone 17-butyrale, 21-acylates), 3,784,692 (the corresponding 17 propionates, 21 acylates), 3,691,214 (17-valerates) and 3,857,941 (17-benzoates). Commercial uses of these compounds has not yet begun in the United States.
Finally, the diacetate of 6,9 difloro-16.beta.methyl prednisolone was discovered by Upjohn to be a very interesting compound subsequently commercialized in the United States. However, none of the other esters seem to have received attention.
An excellent summary of the history of structural modifications of corticosteroids appears as Chapter 9, Anti-inflammatory Steroids, in Anti-Inflammatory Agents, Scheerer (Ed), Academic Press (1974).
This relative activity is surprising since in the 9.alpha.Floro compounds the 16.alpha.-methyl series (Dexamethasone) are known to be more active than the 16.beta.methyl series (betamethasone).
As noted earlier, I have now discovered the 6.alpha.Floro, 16.beta.methyl prednisolone diesters and have found that these compounds are important anti-inflammatory agents, certain of which are of superior potency to 6.alpha.floro, 16.alpha.methyl counterparts in the cotton pellet granuloma rat assay and quite active in the modified McKensie vasoconstriction assay in man. In addition, unlike paramethasone per se, certain members of the series exhibit only limited effect on the thymus and adrenal glands.